Cardiomyopathies that stem from sarcomeric and cytostructural mutations are characterized by adverse cardiac remodeling and predisposition to both arrhythmia and sudden cardiac death. The pathophysiology is complex, as are molecular mechanisms that underlie it. Tackling this complexity systematically demands the development of new tools and models. Here, we outline a multidisciplinary systems biology approach to the study of cardiomyopathy in a model system that leverages the power of rapid genetic manipulation, Drosophila melanogaster. Long valued as a model of cardiac development, application to the study of cardiac disease is its infancy. In a technical breakthrough study, we have succeeded in using proteomic techniques to compile a protein compendium of the Drosophila cardiac tube. Using bioinformatics, we show that it bears hallmarks of heart tissue at the level of cellular componentry, biological processes and molecular functions. We have therefore begun to assess cardiac remodeling in Drosophila models of restrictive and dilated cardiomyopathy arising from sarcomeric lesions using quantitative proteomic methods. This proposal outlines our systems biology approach, by which profiles of protein expression and post-translational modification are translated to testable hypotheses by the application of bioinformatic ontological and network analyses. The perturbation of protein networks will be cross-referenced with simulations from mathematical models of mammalian integrated excitation-contraction coupling and bioenergetics (ECME). Network/Model simulations will be followed up with physiological assessments of aberrant function (e.g. bioenergetics, Ca2+ handling). Preliminary analysis indicates the restrictive cardiomyopathy mutant Mhc5 shows substantial metabolic remodeling, suggesting a possible role for adenosine monophosphate activated protein kinase (AMPK). We outline new technical innovations that we are pursuing as part of the arsenal to measure Drosophila heart performance. The immediate 2-year goal of this exploratory/development grant is to identify a set of novel protein candidates or PTM signatures that lead to altered biological activity in Drosophila models of restrictive and dilated cardiomyopathy. In short, we outline a strategy to streamline the search for genetic suppressors of restrictive and dilated cardiomyopathy i.e. targets for future rapid targeted knockdown and overexpression. Human homologues of these novel modified drosophila proteins may represent novel targets for therapeutic drug design.